Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol

ABSTRACT

A method and composition are disclosed utilizing the pure (R,R) isomer of formoterol, which is a potent bronchodilator with reduced adverse effects, having a low incidence of the development of tolerance and having increased bronchial distribution when administered by inhalation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of earlier application, Ser.No. 08/373,515 filed Jan. 12, 1995, now abandoned, which was acontinuation-in-part of application Ser. No. 08/222,319 filed Apr. 4,1994, now abandoned, which was a continuation of application Ser. No.07/927,458, filed Aug. 10, 1992, now abandoned. This application is alsoa continuation-in-part of presently application, Ser. No. 08/382,744filed Feb. 2, 1995 now abandoned, which was a continuation ofapplication Ser. No. 08/223,798 filed Apr. 6, 1994, now abandoned, whichwas a continuation of application Ser. No. 07/862,907, filed Apr. 3,1992, now abandoned. The entire disclosures of these applications areincorporated herein by reference. Application Ser. No. 07/862,907 claimsthe priority, under 35 USC 119, of Great Britain application 9107196.9,filed Apr. 5, 1991.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter containingoptically pure (R,R) formoterol. These compositions possess potent,long-lasting bronchodilating activity as β-adrenergic agonists whileavoiding or reducing adverse effects including but not limited to muscletremor and tachycardia as well as avoiding or reducing the developmentof tolerance or hypersensitivity on repeated administration. Thecompositions also provide an improved duration of action. This inventionalso relates to methods of treating asthma, bronchitis, emphysema,bronchospasms, and other ailments in patients with obstructive airway orallergic disorders while avoiding adverse effects, development oftolerance or hypersensitivity on repeated administration or a limitedpattern of bronchial distribution when administered by inhalation.

The active compound of these compositions and methods is an opticalisomer of formoterol, which is described by Ida in Arzneim, Forsch. 26,839-842 and 1337-1340 (1976) and in U.S. Pat. No. 3,994,974. Chemically,the active compound is N-hydroxy-5- l-hydroxy-2- 2-(4-methoxyphenyl)methylethyl)amino!ethyl!phenylformamide, which exists as twoenantiomeric pairs of diastereomers. Of these, the R,R diastereomer isthe most active and, when substantially optically pure, will behereinafter referred to as (R,R) formoterol. Formoterol is availablecommercially only as a racemic diastereomer, (R,R) plus (S,S) in a 1:1ratio, and the generic name formoterol refers to this enantiomericmixture. The racemic mixture of (±) formoterol that is commerciallyavailable for administration is a dihydrate of the fumarate salt.

Many organic compounds exist in optically active forms, i.e.. they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L or R and S are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (-) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (-)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. There is no correlation between nomenclaturefor the absolute stereochemistry and for the rotation of an enantiomer.Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is(+). For a given chemical structure, a pair of enantiomers are identicalexcept that they are non-superimposable mirror images of one another. Aspecific stereoisomer may also be referred to as an enantiomer, and amixture of such isomers is often called an enantiomeric or racemicmixture.

Stereochemical purity is of importance in the field of pharmaceuticals,where 12 of the 20 most prescribed drugs exhibit chirality. A case inpoint is provided by the L-form of the beta-adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important since certain isomers mayactually be deleterious rather than simply inert. For example, it hasbeen suggested that the D-enantiomer of thalidomide was a safe andeffective sedative when prescribed for the control of morning sicknessduring pregnancy, while the corresponding L-enantiomer has been believedto be a potent teratogen.

When two chiral centers occur in the same molecule each of them canexist in two possible configurations. This gives rise to fourcombinations: (R,R), (S,S), (R,S) and (S,R). Examination of models willmake more clear the relationship between these four isomers. (R,R) and(S,S) are mirror images of each other and are therefore enantiomerswhich share chemical properties and melting points just like any otherenantiomeric pair. (R,S) and (S,R) are similarly an enantiomeric pair.The mirror images of (R,R) and (S,S) are not, however, superimposable on(R,S) and (S,R). This relationship is called diastereomeric, and (R,R)is a diastereomer of (R,S). Formoterol, having two chiral centers, fallsinto this category. Adrenergic or sympathomimetic drugs are so calledbecause they are understood to exert their effect through their actionon the body's adrenergic receptors of which there are three functionallydivided types, the α, β₁, and β₂ receptors. On the basis of theirinteraction with these three receptor types, the adrenergic orsympathomimetic drugs are in turn classifiable into three groups:

1.1 Non-selective sympathomimetic drugs;

1.2 Non-selective β sympathomimetic drugs; and

1.3 Selective β₂ sympathomimetic bronchodilator drugs.

Drugs of group 1.1 exert both α and β sympathomimetic effects. Theyinclude the drug substances adrenaline and ephedrine. Both adrenalineand ephedrine are known clinically as bronchodilators. Thoughadrenaline, despite side effect induced via its α-sympathomimeticproperties, is still used by some practitioners for the treatment ofacute asthma, both adrenaline and ephedrine have been largely supersededin asthma therapy.

The drugs of group 1.2 have both β₁ and β₂ sympathomimetic activity butno, or only limited, α-sympathomimetic activity. Of the group 1.2 drugs,isoprenaline is the best known representative. Isoprenaline differs fromthe drugs of group 1.3 in its faster onset but shorter duration ofaction and its cardiac stimulating effects which result largely from itsβ₁ activity. Though isoprenaline has previously been extensively used asbronchodilator therapy in asthma, its use has today become clinicallyrestricted. Thus, in the UK, a rise in the rate of asthma death in the1960's believed to have been specifically associated with isoprenalineusage has resulted in discontinuation of its clinical application.

The selective β₂ sympathomimetic bronchodilator drugs of group 1.3(herein referred to for convenience collectively as "Group 1.3 drugs")act, as their name implies, selectively on the β₂ adrenergic receptors.The Group 1.3 drugs include for example, the drug substancesterbutaline, albuterol, fenoterol, isoetharine, metaproterenol and, morerecently, the so-called "long acting selective β₂ sympathomimeticbronchodilator drug substances" formoterol, bambuterol and salmeterol.All of the above recited Group 1.3 drugs are commercially available andclinically used, generally in pharmaceutically acceptable salt form,e.,g. as the sulphate, hydrobromide, hydrochloride, fumarate ormethanesulfonate or, where appropriate, one or other of the hydrateforms thereof.

Group 1.3 drugs characteristically contain as part of their structure anethanolamine or 2-amino-ethanol moiety of formula I ##STR1## in which R₁is an aromatic group. Commonly R₁ is 3,4- or 3,5-dihydroxyphenyl or4-hydroxy-3-hydroxymethylphenyl. R₁ may also be3-formylamino-4-hydroxyphenyl, as in the case of formoterol. R₂ and R₃in formula I are commonly H. Since the formula I moiety comprises atleast 1 asymmetric carbon atom (Cl in formula I), all of the Group 1.3drugs exist in optically active isomeric form, with the chiral carbonatom having the (R) or (S) configuration as designated using theCahn-Ingold-Prelog system (Angew. Chem. Intern. Ed. 5, 385-415 (1966)!.When the C1 carbon atom is the sole asymmetric carbon atom present,Group 1.3 drugs thus exist as individual (R) or (S) enantiomers or inracemic (RS)! form, i.e. as a 50:50 mixture of the (R) and (S)enantiomers.

Individual Group 1.3 drugs in which R₂ in the formula I moiety is otherthan H, or in which the remainder of the molecule includes an asymmetriccarbon atom (e.g. formoterol) exist in a variety of isomeric forms, i.e.in individual (R,R), (S,S (R,S) and (S,R) isomeric form, as racemic(RS,RS) and (RS,SR)! mixtures comprising the (R,R) plus (S,S) and (R,S)plus (S,R) enantiomeric pairs, as well as in the form of diastereomericmixtures comprising all four isomeric forms.

The Group 1.3 drugs can be administered orally, parenterally or (mostcommonly) by inhalation, e.g. using nebulizers or metered aerosoldevices or as inhaled powders. Inhalation of Group 1.3 drugs presentlyrepresents the mainstay of bronchodilator therapy for the treatment ofasthma of all grades of severity. The duration of bronchodilatationinduced by the majority of Group 1.3 drugs is relatively short and theyare employed to relieve asthma attack as and when it occurs. Asindicated above, the more recently introduced Group 1.3 drugs, such asformoterol, are characterized by their longer duration of action andhence apparent reduced frequency of dosaging required.

Although the Group 1.3 drugs are effective and generally seem to be welltolerated, their safety, especially at high dosages, has been questionedover many years and numerous reports have appeared on the adverseeffects of Group 1.3 drug therapy (see e.g. Paterson et al: AmericanReview of Respiratory Disease 120, 844-1187 (1979) especially at page1165 et seq.). More recently, from New Zealand, where a continuingincrease in asthma death has been recorded, two case control studiesreported in The Lancet have linked increase in asthma mortality to useof the Group 1.3 drug, fenoterol--see in particular: Editorial "β₂agonists in asthma: relief, prevention, morbidity", Lancet 336,1411-1412 (1990). A subsequently reported Canadian study finds that theuse of inhaled Group 1.3 drugs, principally fenoterol and albuterol, isassociated with "an increased risk of the combined outcome of fatal andnear-fatal asthma, as well as of death from asthma alone"--see Spitzeret al., New England J. Med. 326 (8), 501-506 (1992) and the Editorial tothe same issue at page 560.

Various possible explanations for observed episodes of increased airwayobstruction, arterial hypoxaemia or "anomalous" or "paradoxical"bronchospasm, as well as increased morbidity associated with Group 1.3drug usage, in particular long term/high dose usage, have been proposed.These have included, for example, reactive myogenic tone, increasedinflammatory burden, adrenoceptor tachyphylaxis and induction of airwayhyperreactivity, as well as the involvement of spasmogenic drugmetabolic products or long term influence of aerosol spraypropellants--see e.g. Paterson et al. loc. cit. and Morley et al., Eur.Respir. J. 3, 1-5 (1990).

There is mounting concern within the medical profession as to thepotential dangers of Group 1.3 drug usage in asthma therapy. To quotethe Lancet editorial already referred to:

"These studies raise serious question about the use of β₂ agonists i.e.Group 1.3 drugs!. The findings of Sears et al. could be interpreted assupporting the current trend towards earlier use of corticosteroids andother preventers of inflammation for asthma therapy! rather thanperseverance with an escalating bronchodilator regimen. The findings ofthe Nottingham and Dunedin groups also indicate that there is some wayto go before long acting β₂ agonist preparations such as salmeterol andformoterol can be unreservedly recommended for routine use in themanagement of asthma. There seem to be clear advantages of complianceand possibly of anti-inflammatory activity associated with such agents,but the potential for adverse effects cannot be ignored. Cliniciansresearchers and pharmaceutical companies must now attempt to redefinethe use of β₂ agonists in asthma." Emphasis added.!

Equally there has been evident inability or reluctance to conceive ofany problem in relation to Group 1.3 drug therapy as being inherent inGroup 1.3 drugs themselves or as hitherto employed--cf. the following,taken from the editorial in the New England Journal of Medicine alsopreviously referred to:

"Although . . . too much reliance is placed on beta-agonists (Group 1.3drugs!, it is difficult to believe that the problem is related directlyto the more regular use of inhaled beta-agonists."

While the suitability, in particular of high-dose or long-term, Group1.3 drug therapy has long been a subject of debate and, more recently,acute question, the practice of administering drugs of this group asracemic mixtures has continued. This practice has been accepted by drugregistration authorities world-wide and even the most recentlyintroduced of the Group 1.3 drugs have been developed for clinical useas racemic mixtures. This practice is based upon the assumption orunderstanding that the non-bronchodilator component of the racemicmixture, i.e. the bronchodilatorily less or inactive enantiomer(distomer) is devoid of any relevant drug effect and can thus beadministered together with the bronchodilatorily active isomer (eutomer)essentially as inactive ballast and without risk to the patient. Theteaching of the present invention thus stands in stark opposition tolong, widely established and continuing practice. The present inventionthus runs contrary to the wisdom of the art. In that the Group 1.3 drugsclearly offer very considerable potential benefit for bronchodilatorusage in asthma, the need to find a means of avoiding, ameliorating orrestricting disadvantages inherent in their use is urgent and crucial.By meeting this need, the present invention may be anticipated to bringimmeasurable benefit both to the medical profession and the world asthmapopulation.

Formoterol, which is the subject of the present invention, is availableonly as a racemic mixture of the (R,R) and (S,S) diastereomers. Trofastet al. Chirality 3, 443-450 (1991)! have described the preparation ofeach of the substantially pure isomers. They concluded that "Since the(S,S)-enantiomer is practically inactive there is from this point ofview no reason for its removal from the racemate in pharmaceuticalpreparations . . . "

Formoterol's primary use is as a long-acting bronchodilator for therelief of reversible bronchospasm in patients with obstructive airwaydisease such as asthma, bronchitis and emphysema.

Asthma, bronchitis and emphysema are known as Chronic ObstructivePulmonary Diseases (COPD). COPD is characterized as generalized airwaysobstruction, particularly of small airways, associated with varyingdegrees of symptoms of chronic bronchitis, asthma, and emphysema. Theterm COPD was introduced because these conditions often coexist, and itmay be difficult in an individual case to decide which is the majorcondition producing the obstruction. Airways obstruction is defined asan increased resistance to airflow during forced expiration. It mayresult from narrowing or obliteration of airways secondary to intrinsicairways disease, from excessive collapse of airways during a forcedexpiration secondary to pulmonary emphysema, from bronchospasm as inasthma, or may be due to a combination of these factors. Althoughobstruction of large airways may occur in all these disorders,particularly in asthma, patients with severe COPD characteristicallyhave major abnormalities in their small airways, namely those less than2 mm internal diameter, and much of their airways obstruction issituated in this zone. The airways obstruction is irreversible exceptfor that which can be ascribed to asthma.

Asthma is a reversible obstructive lung disorder characterized byincreased responsiveness of the airways. Asthma can occur secondarily toa variety of stimuli. The underlying mechanisms are unknown, butinherited or acquired imbalance of adrenergic and cholinergic control ofairways diameter has been implicated. Persons manifesting such imbalancehave hyperactive bronchi and, even without symptoms, bronchoconstrictionmay be present. Overt asthma attacks may occur when such persons aresubjected to various stresses, such as viral respiratory infection,exercise, emotional upset, nonspecific factors (e.g., changes inbarometric pressure or temperature), inhalation of cold air or irritants(e.g., gasoline fumes, fresh paint and noxious odors, or cigarettesmoke), exposure to specific allergens, and ingestion of aspirin orsulfites in sensitive individuals. Psychologic factors may aggravate anasthmatic attack but are not assigned a primary etiologic role.

Persons whose asthma is precipitated by allergens (most commonlyairborne pollens and molds, house dust, animal danders) and whosesymptoms are IgE-mediated are said to have allergic or "extrinsic"asthma. They account for about 10 to 20% of adult asthmatics; in another30 to 50%, symptomatic episodes seem to be triggered by non-allergenicfactors (e.g., infection, irritants, emotional factors), and thesepatients are said to have nonallergic or "intrinsic" asthma. In manypersons, both allergenic and nonallergenic factors are significant.Allergy is said to be a more important factor in children than inadults, but the evidence is inconclusive.

Chronic bronchitis (unqualified) is a condition associated withprolonged exposure to nonspecified bronchial irritants and accompaniedby mucus hypersecretion and certain structural changes in the bronchi.Usually associated with cigarette smoking, it is characterizedclinically by chronic productive cough. The term chronic obstructivebronchitis is used when chronic bronchitis is associated with extensiveabnormalities of the small airways leading to clinically significantairways obstruction. (Pulmonary emphysema is enlargement of the airspaces distal to terminal nonrespiratory bronchioles, accompanied bydestructive changes of the alveolar walls.) The term chronic obstructiveemphysema is used when airways obstruction is also present and where itis clear that the major features of the disease can be explained byemphysematous changes in the lungs.

Many of the β₂ agonists cause somewhat similar adverse effects. Theseadverse effects include but are not limited to the central nervoussystem symptoms such as hand tremors, muscle tremors, nervousness,dizziness, headache and drowsiness; respiratory side effects such asdyspnea, wheezing, drying or irritation of the oropharynx, coughing,chest pain and chest discomfort; cardiovascular effects such aspalpitations, increased heart rate, and tachycardia. According toTrofast et al. (op. cit.) (R,R) formoterol is primarily a chronotropicagent in vitro with inotropic effects showing up at higherconcentrations. The chronotropic effects are reported at concentrationsthat are higher than those at which relaxation of tracheal muscle(bronchodilation) is seen. β-Agonists (e.g. dobutamine) are known ingeneral to exhibit inotropic activity. In addition, racemic β₂ -agonistscan cause angina, vertigo, central stimulation and insomnia, airwayhyperreactivity (hypersensitivity), nausea, diarrhea, dry mouth andvomiting. As with other pharmaceuticals β₂ -agonists sometimes causesystemic adverse effects such as weakness, fatigue, flushed feeling,sweating, unusual taste, hoarseness, muscle cramps and backaches.

Furthermore, patients have a tendency to develop a tolerance to thebronchodilating effect of the racemic mixture of formoterol. This isrelated to desensitization, which is one of the most clinicallysignificant phenomena involving the beta-adrenergic receptor. It hasbeen observed that patients in prolonged beta-agonist therapy have atendency to increase the dosage of drug they use. This occurs becauseafter prolonged administration, the beta-receptor appears to becomedesensitized to the agonist, thus requiring larger doses of the compoundto effect an equivalent physiological response.

The problem of desensitization is especially significant in thetreatment of diseases involving bronchospasms, such as asthma. Thetreatment of asthma usually involves the self-administration eitherorally or by aerosol, of beta-adrenergic agonists such as the racemic(R,R) (S,S) mixture of formoterol These agonists mediate bronchodilationand promote easier breathing. Asthmatic patients utilizing β-agonistsfor a prolonged time gradually increase the self-administered dose inorder to get a sufficient amount of bronchodilation and relief inbreathing. As a result of this increased dosage, the agonistconcentration builds to a sufficient level so as to enter the peripheralcirculation where it acts on the beta receptors of the heart andvasculature to cause cardiovascular stress and other adverse effects.

Moreover, when administering the racemic mixture of formoterol byinhalation, because of particle size and air flow distributioncharacteristics of the racemic mixture of formoterol, the distributionof the compound into the smaller bronchioles is limited, which resultsin a decreased effectiveness of the compound.

It is therefore desirable to find a compound with the therapeuticcharacteristics of formoterol which would not have the above describeddisadvantages.

SUMMARY OF THE INVENTION

It has now been discovered that the (R,R) isomer of formoterol is aneffective bronchodilator that does not have certain adverse effectsassociated with the administration of the racemic mixture of (R,R) and(S,S) formoterol. The present invention includes administering to ahuman (R,R) formoterol to cause bronchodilation and to decrease saidadverse effects. Furthermore, it has also been discovered that byadministering only the (R,R) isomer of formoterol there is decreasedtolerance and hypersensitivity to the compound, relative to that seenwhen the racemic mixture of formoterol is administered. In addition, ithas been discovered that by administering the (R,R) isomer of formoterolby inhalation, it is possible to obtain improved distribution of thecompound in the smaller bronchioles which results in an increasedbronchodilating effect. In addition, an increased duration of thebeneficial effects is observed upon administration of the substantiallypure (R,R) enantiomer, as compared to administration of the racemicdrug.

The present invention also includes novel compositions of mattercontaining optically pure (R,R) formoterol which is useful as abronchodilator. These novel compositions also avoid the above describedadverse effects, increased tolerance or limited pattern of distributionwhen administered by inhalation, associated with the racemic mixture offormoterol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of eliciting a bronchodilatoreffect while avoiding the concomitant liability of adverse effects,development of tolerance, or limited pattern of bronchial distributionwhen administered by inhalation, which comprises administering to ahuman in need of bronchodilation an amount sufficient to alleviatebronchospasms, but insufficient to cause said adverse effects,development of tolerance, hypersensitivity or limited pattern ofbronchial distribution when administered by inhalation, of (R,R)formoterol or a pharmaceutically acceptable salt thereof, substantiallyfree of its (S,S) stereoisomer. The bronchodilator effects are achievedby utilizing the highly potent β-adrenergic effects of the (R,R) isomerof formoterol while substantially limiting the adverse effects,development of tolerance, hypersensitivity or limited pattern ofbronchial distribution when administered by inhalation, by decreasing oreliminating the amount of (S,S) isomer in the composition.

As hereinbefore described in relation to formula I, C1 in the eutomer ofGroup 1.3 drugs characteristically has the (R) configuration. In thecase of Group 1.3 drugs having two asymmetric carbon atoms, the eutomercould thus be the (R,R) or (R,S) isomer. Although we have found that itis the (R,R) enantiomer which has the greatest bronchodilator potency,Group 1.3 drugs having two asymmetric carbon atoms have hitherto beenused in the clinic generally in the form of the (RS,RS) racemic mixture.

The present invention also encompasses a bronchodilator composition forthe treatment of a patient in need of bronchodilating therapy whichcomprises an amount sufficient to alleviate bronchospasms butinsufficient to cause adverse effects, development of tolerance orlimited bronchial distribution when administered by inhalation, of (R,R)formoterol or a pharmaceutically acceptable salt thereof, substantiallyfree of its (S,S) stereoisomer.

The racemic mixture of formoterol causes bronchial smooth musclerelaxation and modulates inhibition of mediator release effect; however,this racemic mixture causes adverse effects, leads to the development oftolerance and the development of hypersensitivity and results in alimited pattern of bronchial distribution when administered byinhalation. Utilizing the (R,R) isomer of formoterol results indiminished adverse effects, decreased development of tolerance andincreased bronchial distribution when the compound is administered byinhalation. Thus, it is much more desirable to use the (R,R) isomer offormoterol when treating asthma, bronchitis, emphysema or to alleviatebronchospasms.

Furthermore, although there is some variability from one patient toanother, it is generally observed that, by administering an effectiveamount of only the (R,R) isomer of formoterol it is possible toaccomplish a more "targeted" therapy. A more "targeted" therapy meansthat by using the (R,R) isomer the compound's activity can be takenadvantage of without also having consequences of the pharmacologiceffects of the (S,S) isomer which are observed upon administration ofthe racemic mixture. This is important since it is not desirable for allpatients to be administered a compound with such a multifaceted spectrumof activity.

The present invention provides a method or use for the treatment ofinflammatory airways disease, in particular for effectingbronchodilatation, e.g. as a means of alleviating airways obstruction,in particular acute airways obstruction, e.g. asthma attack, occurringin such disease. The invention thus provides symptomatic, rather thanprophylactic, therapy for such disease. The teaching of the presentinvention is applicable in the therapy of inflammatory or obstructiveairways disease, in particular any such disease for which Group 1.3 drugtherapy is commonly practiced, for example chronic obstructive pulmonarydisease, e.g. consequential to cystic fibrosis, emphysema and,especially, chronic bronchitis and, most especially, asthma.

The present invention avoids deleterious side effects hereinbeforeresulting or observed in, e.g. asthmatic, patients consequent toconventional clinical usage of Group 1.3 drugs as racemic mixtures. Inparticular the invention provides means to avoid, ameliorate or restrictdeleterious side effects, e.g. side effects deleterious to the airways.Thus the invention provides means to avoid, ameliorate or restrictexacerbation of disease status, for example basal disease, e.g. basalasthmatic, status or to avoid, ameliorate or restrict compromise ordeterioration of lung function, or any other side effect concomitant toconventional clinical usage, for example "anomalous", "rebound" or"paradoxical" bronchospasm and, especially, increase in airwayobstruction, exacerbation of late asthmatic response or non-specificbronchial reactivity or arterial hypoxemia. Without limiting the presentinvention to any specific theory or mode of action, the presentinvention is in particular to be understood as providing a means for theavoidance, amelioration or restriction of exacerbation of airwayshyperreactivity and/or of an inflammatory or other event associatedwith, or which is an etiological component of, inflammatory orobstructive airways disease, e.g. asthma. Such events are to beunderstood as including for example, inflammatory cell infiltration ofthe lungs or airways, connective tissue deposition or smooth musclehyperplasia within the lungs or airways or other morphological changeassociated with asthmatic status. The present invention also provides ameans of preventing or reducing morbidity, e.g. asthma morbidity,ascribable to conventional, e.g. high dosage or long term, Group 1.3drug usage.

The present invention is especially applicable in the therapy ofbronchial asthma of whatever type or genesis. It is applicable to bothintrinsic and extrinsic asthma. It is especially applicable to thetreatment of allergic or atopic (i.e. IgE-mediated) asthma or non-atopicasthma, as well as exercise induced asthma, occupational asthma, asthmainduced following bacterial infection or drug, e.g. aspirin, ingestionand other non-allergic asthmas. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting chronic cough or wheezing symptoms, inparticular at night, and diagnosed or diagnosable as "wheezy infants",i.e. as embracing the treatment of "wheezy infant syndrome". otherdiseases to which the present invention is in particular applicableinclude for example chronic obstructive pulmonary or airways disease(COPD or COAD).

The term "adverse effects" includes but is not limited to hand tremors,muscle tremors, nervousness, palpitations, tachycardia, increased heartrate, dyspnea, coughing, chest pain, chest discomfort, drying orirritation of the oropharynx and wheezing. Also included in the term"adverse effects" are headaches, dizziness, fatigue, hoarseness,backaches, nausea, vomiting, drowsiness, weakness, flushed feeling,sweating, unusual taste, muscle cramps, weakness, angina, vertigo,central stimulation, hypersensitivity and insomnia.

The term "substantially free of the (S,S) stereoisomer" as used hereinmeans that the composition contains at least about 90% by weight of(R,R) formoterol and 10% or less by weight of (S,S) formoterol. In amore preferred embodiment the composition contains at least 99% byweight (R,R) formoterol and 1% or less of (S,S) formoterol. In the mostpreferred embodiment the composition contains greater than 99% by weightof (R,R) formoterol and less than 1% by weight of (S,S) formoterol.

The term "eliciting a bronchodilator effect" means relief from thesymptoms associated with obstructive airway diseases, which include butare not limited to respiratory distress, wheezing, coughing, shortnessof breath, tightness or pressure in the chest and the like.

The term "development of tolerance" means that when administering theracemic mixture of formoterol in repeated dosage or over a period oftime, the amount of the compound given to the patient must be increasedin order to achieve the same effect as the lower dosage given at anearlier time.

The term "limited pattern of bronchial distribution when administered byinhalation" means that therapeutically efficacious quantities cannotpenetrate into smaller bronchioles.

The mixture of formoterol isomers can be prepared according to U.S. Pat.No. 3,994,974. The diasteromers may be separated as described by Muraseet al. Chem. Pharm. Bull. 25, 1368-13 (1977). The individual isomers offormoterol may be obtained as described by Trofast et al. (op. cit.) bystereocontrolled synthesis from optically active starting material or byresolution of a mixture of enantiomers (i.e., the racemic mixture) usingconventional means, such as an optically active resolving acid. Otherstandard methods of resolution known to those skilled in the artincluding but not limited to simple crystallization and chromatographicresolution can be used. (See for example, Stereochemistry of CarbonCompounds, E. L. Eliel, McGraw Hill 1962; "Tables of Resolving Agents,"S. A. Wilen and Lochmuller, L. H. et al., 1975, J. Chromatogr. 113(3):283-302.) Additionally, the optically pure (R,R) isomer can be preparedfrom the racemic mixture by enzymatic biocatalytic resolution. See, forexample, U.S. Pat. Nos. 5,057,427 and 5,077,217, the disclosures ofwhich are incorporated herein by reference.

The magnitude of a prophylactic or therapeutic dose of (R,R) formoterolin the acute or chronic management of disease will vary with theseverity of the condition to be treated, and the route ofadministration. The dose, and perhaps the dose frequency, will also varyaccording to the age, body weight, and response of the individualpatient. In general, the total daily dose ranges when administered byinhalation, for the conditions described herein, is from about 1 μg toabout 100 μg, in single or divided doses. Preferably, a daily dose rangeshould be between about 6 μg to about 25 μg, in single or divided doses,while most preferably, a daily dose range should be between about 12 μgto about 25 μg, in from two to four divided doses. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about3 μg to about 12 μg, and increased up to about 2×12 μg or higherdepending on the patient's global response. When administered orally,preferably as a tablet, the preferred dose range is from 0.1 to 1.0 mgper day. It is further recommended that children, and patients over 65years, and those with impaired renal, or hepatic function, initiallyreceive low doses, and that they be titrated based on individualresponse(s) and blood level(s). It may be necessary to use dosagesoutside these ranges in some cases as will be apparent to those skilledin the art. Further, it is noted that the clinician or treatingphysician would know how and when to interrupt, adjust, or terminatetherapy in conjunction with individual patient response.

The terms "an amount sufficient to alleviate bronchospasms butinsufficient to cause said adverse effects" are encompassed by theabove-described dosage amounts and dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of (R,R) formoterol. For example, oral,rectal, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, patches, and the like.

The pharmaceutical compositions of the present invention comprise (R,R)formoterol as the active ingredient, or a pharmaceutically acceptablesalt thereof, and may also contain a pharmaceutically acceptablecarrier, and optionally, other therapeutic ingredients.

The term "pharmaceutically acceptable salts" or "a pharmaceuticallyacceptable salt thereof" refer to salts prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids and organic acids.Suitable pharmaceutically acceptable acid addition salts for thecompound of the present invention include acetic, benzenesulfonic(besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, and the like. The fumaric acid salt is particularlypreferred.

The compositions of the present invention include compositions such assuspensions, solutions and elixirs; aerosols; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like. Thecompositions include compositions suitable for oral, rectal, parenteral(including subcutaneous, transdermal, intramuscular, and intravenous)and inhalation, although the most suitable route in any given case willdepend on the condition being treated and the nature and severity ofthat condition. The most preferred routes of the present invention are:(1) oral by either tablets or capsules, (2) inhalation and (3)transdermal by patch. They may be conveniently presented in unit dosageform and prepared by any of the methods well-known in the art ofpharmacy.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are hereby incorporated by reference.

The invention is further defined by reference to the following examplesdescribing in detail the pharmacological characterization of thecompound, and the preparation of compositions of the present invention.It will be apparent to those skilled in the art, that manymodifications, both to materials, and methods, may be practiced withoutdeparting from the purpose and interest of this invention.

EXAMPLES Procedure 1

β-Adrenergic Receptor Phosphorylation by β-Adrenoreceptor Kinase.Reconstituted β-adrenergic receptor is incubated with β-adrenoreceptorkinase in a buffer containing 20 mM Tris-HCl, H 7.5, 2 mM EDTA, 20 mMNaCl, 6 mM MgCl₂, 6 mM sodium phosphate, 0.5 mM ascorbic acid 60 μM γ-³²P!ATP at 30° C. The incubations also contain varying concentrations ofone of the following: buffer (control), (-)-isoproterenol,R,R-formoterol, S,S-formoterol or racemic formoterol. The incubationsare stopped by the addition of SDS sample buffer followed byelectrophoresis on 10% homogeneous polyacrylamide gels. Stoichiometriesof phosphorylation are determined by cutting and counting the dried gelas described in Benovic J. L. et al. J. Biol. Chem. 9026-9032 (1987)!.

Procedure 2

Purification of component proteins. The p-adrenergic receptor fromhamster lung is purified to >95% homogeneity by sequential affinitychromatography and high performance liquid chromatography as describedby Benovic et al. Biochemistry 23, 4510-4518 (1984)!. The stimulatoryguanine nucleotide regulatory protein is purified from membranes derivedfrom bovine cerebral cortex. The membranes, solubilized with 1% cholate,are centrifuged and the resulting supernatant chromatographed onDEAE-Sephacel, Ultrogel AcA34, octyl-Sepharose, and hydroxyapatite, witha final step on DEAE-Sephacel, as adapted from Strittmater and NeerProc. Natl. Acad. Sci. 77, 6344-6348 (1980)!. The resulting proteinshould be 50-90% pure by Coomassie Blue staining of polyacrylamide gels.The catalytic moiety of adenylate cyclase is solubilized from bovinecaudate with sodium cholate and isolated from the other components ofthe system by Sepharose 6B chromatography as described in Strittmaterand Neer (op. cit.). β-Adrenoreceptor kinase is purified from bovinecerebral cortex. The tissue is homogenized, and the resulting high speedsupernatant fraction is precipitated with 13-26% ammonium sulfate. Thismaterial is then chromatographed on Ultrogel AcA34, DEAE-Sephacel, andCM-Fractogel. The preparations used should be 10-20% pure as judged byCoomassie Blue staining of SDS-polyacrylamide gels.

Assay for adenylate cyclase activity. The co-reconstitution of thepurified proteins is carried out as described in Cerione et al. J. Biol.Chem. 259; 9979-9982 (1984). The pelleted proteins are incubated for 15min. at 37° C. in 30 mM Tris-HCl, pH 7.5 containing 1 mM ATP, 2 μCi ofα-³² P!ATP 0.14 mM cAMP, 100 mM sucrose, 0.4 mM dithiothreitol, 2.8 mMphosphoenol pyruvate, 5.2 μg/mL pyruvate kinase, 10 μg/ml of myokinase,5 mM MgCl₂, and varying concentrations of racemic formoterol, (R,R)formoterol and (S,S) formoterol (total volume=0.5 mL). The reaction isstopped by the addition of 0.25 mL 2% sodium dodecylsulfate containing40 mM ATP and 1.4 mM cAMP at pH 7.5. Water (0.5 mL) is added to eachreaction tube and the contents placed on a Dowex 50AG WX4 resin. Theeluate from the columns plus two successive water washes (1.0 mL) arediscarded. The columns are then eluted with 3 mL water and the eluatescollected in test tubes. Each fraction is diluted with 0.2 mL of 1.5Mimidazole HCl, pH 7.2. The tubes from each concentration (run intriplicate) are combined and decanted into columns containing 0.6 gneutral alumina that has been previously washed with 0.1 M imidazoleHCl, pH 7.5. The eluate is collected in scintillation vials containing12 mL Aquasol®. After the columns are completely drained, they arewashed with an additional 1 mL of 0.1 M imidazole HCl, pH 7.5 which iscollected in the same scintillation vials. The concentration of ³²P-cAMP is determined in each sample.

The metabolic rates of the racemate and the isomers of formoterol havebeen studied in human liver tissues. It was unexpectedly found that themetabolic rate is significantly slower for (R,R) formoterol than for theracemate and for the SS-isomer. These new findings show that theclearance (V_(max) /K_(m)) was 152 for (R,R) formoterol, 381 for (S,S)formoterol and 489 for (R,R/S,S) formoterol. It is possible to calculatethe relative biological half-lives of the RR-isomer and the racematefrom these data, using the formula C1=Vd×0.693/t_(1/2). Assuming thesame distribution volume for all three compounds, the relativehalf-lives are 4.6 for (R,R) formoterol and 1.4 for (R,R/S,S)formoterol. Thus, the half-life of (R,R) formoterol is approximatelythree times longer than the half-life of the racemate. This demonstratesa significant advantage of the pure RR enantiomer in terms of itsduration of action as well as diminution of side effects.

EXAMPLE 1

    ______________________________________                                        ORAL FORMULATION                                                              Tablets:                                                                                         Quantity per Tablet                                                           (mg.)                                                      Formula            A          B                                               ______________________________________                                        (R,R) formoterol    0.12       0.25                                           Lactose            41.38      41.25                                           Cornstarch          3.0        3.0                                            Water (per thousand Tablets)*                                                                    30.0  ml   30.0  ml                                        Cornstarch          5.00       5.00                                           Magnesium Stearate  0.50       0.50                                                              50.00      50.00                                           ______________________________________                                         *The water evaporates during manufacture                                 

The formoterol is blended with the lactose until a uniform blend isformed. The smaller quantity of cornstarch is blended with the water toform the resulting cornstarch paste. This is then mixed with saiduniform blend until a uniform wet mass is formed. The remainingcornstarch is added to the resulting wet mass and mixed until uniformgranules are obtained. The granules are then screened through a suitablemilling machine, using a 1/4 inch stainless steel screen. The milledgranules are then dried in a suitable drying oven until the desiredmoisture content is obtained. The dried granules are then milled througha suitable milling machine, using 1/4 mesh stainless steel screen. Themagnesium stearate is then blended and the resulting mixture iscompressed into tablets of desired shape, thickness, hardness anddisintegration.

EXAMPLE 2

    ______________________________________                                        ORAL INHALATION                                                                                Quantity contained in Each                                                    Metered Dose Dispenser                                       Formula          7.5 mL (10.5 g) Canister                                     ______________________________________                                        (R,R) formoterol    1.8       mg                                              trichloromonofluoromethane                                                                        5.16      g                                               dichlorodifluoromethane                                                                           5.16      g                                               sorbitan trioleate  0.105     g                                               ______________________________________                                    

The metered dose dispenser contains micronized (R,R) formoterol fumaratedihydrate in suspension. Each actuation delivers 6 μg of (R,R)formoterol fumarate dihydrate from the mouthpiece. Each canisterprovides about 300 inhalations.

What is claimed is:
 1. A method for eliciting a bronchodilator effectwhile avoiding the concomitant liability of hypersensitivity whichcomprises administering to a human in need of bronchodilation an amountof (R,R)-formoterol, or a pharmaceutically acceptable salt thereof,sufficient to alleviate bronchospasms but insufficient to causehypersensitivity, said (R,R)-formoterol containing at least 99% byweight of (R,R)-formoterol and less than 1% by weight of(S,S)-formoterol.
 2. The method of claim 1 wherein (R,R) formoterol isadministered by subcutaneous injection, intravenous infusion,inhalation, transdermal delivery or oral administration.
 3. The methodaccording to claim 2 wherein the amount administered by inhalation isabout 1 μg to about 100 μg per day.
 4. The method according to claim 2wherein the amount administered orally is about 0.1 to about 1 mg perday.
 5. The method according to claim 1 wherein (R,R) formoterol orpharmaceutically acceptable salt thereof is administered together with apharmaceutically acceptable carrier.
 6. A method according to claim 2wherein (R,R) formoterol fumarate dihydrate is administered.
 7. A methodaccording to claim 3 wherein said amount is administered in divideddoses from two to four times a day.
 8. A bronchodilator composition inthe form of a tablet, capsule, transdermal patch or aerosol, whichcomprises a pharmaceutically acceptable carrier suitable for a tablet,capsule, transdermal patch or aerosol and an amount of (R,R)-formoterol,or a pharmaceutically acceptable salt thereof, sufficient to alleviatebronchospasms but insufficient to cause hypersensitivity, said(R,R)-formoterol containing at least 99% by weight of (R,R)-formoteroland less than 1% by weight of (S,S)-formoterol.
 9. A compositionaccording to claim 8 adapted for administration by inhalation whereinthe amount of (R,R) formoterol is about 6 μg to about 25 μg.
 10. Acomposition according to claim 9 which comprises (R,R) formoterolfumarate dihydrate.
 11. A composition according to claim 8 adapted fororal administration.
 12. A composition according to claim 11 wherein theamount of formoterol in an oral dosage form is from about 0.1 mg toabout 1 mg.
 13. A composition according to claim 8 adapted fortransdermal administration.
 14. A method for eliciting a bronchodilatoreffect that is more than twice the duration of the bronchodilator effectof a comparable dose of racemic formoterol, which comprisesadministering to a human in need of bronchodilation an amount of(R,R)-formoterol, or a pharmaceutically acceptable salt thereof,sufficient to alleviate bronchospasms, said (R,R)-formoterol producing abronchodilator effect that is more than twice the duration of thebronchodilator effect of a comparable dose of racemic formoterol, andsaid (R,R)-formoterol containing at least 99% by weight of(R,R)-formoterol and less than 1% by weight of (S,S)-formoterol.
 15. Amethod for eliciting a bronchodilator effect that is of longer durationthan the bronchodilator effect of a comparable dose of racemicformoterol, which comprises administering to a human in need ofbronchodilation an amount of (R,R)-formoterol, or a pharmaceuticallyacceptable salt thereof, sufficient to alleviate bronchospasms, said(R,R)-formoterol producing a bronchodilator effect that is of longerduration than the bronchodilator effect of a comparable dose of racemicformoterol, and said (R,R)-formoterol containing at least 99% by weightof (R,R)-formoterol and less than 1% by weight of (S,S)-formoterol.